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INFLAMMATION, MACROPHAGES AND CANCER
Balkwill and Mantovani, Lancet 2001
RUDOLF LUDWIG KARL
VIRCHOW (1821-1902)
(Mantovani et al. Lancet 2008; Nature 2008)
30
20
10
0
0 24 48 72
hours
IN VITRO
Control
mFS6 + TAM
Control
mFS6 + TAM
[3H
] T
dR
upta
ke(c
pm
x 10
-3)
In Vitro and in vivo
(Mantovani A. 1978) (Bottazzi et al Science 1983)
Ilya Mechnikov (1845-1916)The Nobel Prize in Physiology and Medicine
1908
(TAM: Robert Evans, Transplantation, 1972;
Evans and Alexander, Nature, 1970)
Farbstudie Quadrate, Wassily Kandinsky, 1913
M1
M2
(Selected reviews: Sica and Mantovani J Clin Inv 2012; Biswas and Mantovani, Nature Immunol 2010;
Murray et al Immunity 2014; Mantovani and Allavena J Exp Med 2015; Mantovani Nature Immmunol 2016)
M2-like M1-like
«A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation)»Biswas et al., Blood 2006
(e.g. Mantovani, Sica, Allavena, Balkwill, Nature, 2008; Mantovani, Nature, 2009; Hanahan and Weinberg, Cell, 2000; Cell, 2011; Reis et al, Nature Rev Immunol, 2018; Bonavita et al, Cell, 2015)
Complement / PTX3
Cellular Innate Immunity
Humoral Innate Immunity
The macrophage balance in cancer
(Mantovani et al, Nature Rev. Clin. Oncol., 2017; Mantovani and Longo,New England J Med., 2018; Mantovani et al, Annu Rev Pathol, Under revision)
Mechanisms of TAMmediated immune suppression
(Mantovani et al, Nature Rev Clin Oncology, 2017; Mantovani and Ceresoli Lancet Oncol 2018)
NK cell
THE IL-1 RECEPTOR (ILR)
superfamily
(for a review on IL-1/IL-1R family Garlanda et al Immunity 2013; Immunity 2019 in press)
(Mantovani et al, Immunity, 2019 In press)
The dual role of IL-1 / IL-1R family members in cancer
Macrophage-targeting antitumour treatment approaches
Mantovani et al, Nature Rev Clin Oncol, 2017
Trabectedin: Chemo and macrophage targeting in one moleculeGermano, ...D’Incalci, Mantovani, Allavena Cancer Cell 2013;
Macrophage-targeting antitumour treatment approaches
Mantovani et al, Nature Rev Clin Oncol, 2017
Trabectedin: Chemo and macrophage targeting in one moleculeGermano, ...D’Incalci, Mantovani, Allavena Cancer Cell 2013;
IFNγ IMMUNOTHERAPY IN OVARIAN CANCER
PATIENTS WITH MINIMAL RESIDUAL DISEASE (i.p.)
Allavena et al., Cancer Res 1990; Colombo et al., Int J Cancer 1992; Pujade-Lauraine et al., Bull Cancer 1993; J C O, 1996
Advanced cancer (7 pts) Minimal residual disease
Biological response in minimalresidual disease: Pt2 (CR)
8 pts; full trial 108 pts
Tumor-Associated Macrophages in Cancer Progression and as Therapeutic Targets.
Macrophages can exert dual function in patients with cancer, depending on the activation state and therapy. During tumor progression,
protumor functions prevail. C-MYC, an oncogene that often drives the proliferation of neoplasms, also induces the expression of CD47.
Negative signals delivered by the signal regulatory protein α (SIRPα) to macrophages through CD47 prevent their participation in tumor killing.
In the presence of antitumor monoclonal antibodies (anti-CD20; rituximab), blocking the CD47–SIRPα checkpoint unleashes macrophage-
mediated tumor-cell phagocytosis and killing. The same pathway activates effective adaptive immunity. PD-L1 denotes programmed death
ligand 1. (Mantovani and Longo, New England J. Med. 2018; on Advani et al NEJM 2018)
(Mantovani et al, Immunity 2019, in press)
The IL-1 / IL-1R family
RESISTANCE TO SELECTED MICROBES (eg A. fumigatus, P. aeruginosa) –REGULATION OF INFLAMMATION and REPAIR – ADAPTIVE IMMUNITY
ASN220
Chr 3q25mRNA 1866 bp
Prot 381 aa
PTX signature(HxCxS/TWxS)
Ex 1 Ex 2 Ex 3
SP NTD PTX
OmpAMen B
components
C1qFactor H
FcγR P-selectinFicolinsMBL
Microbe recognition
C activationand regulation of
inflammation
Opsonization Regulation ofleukocyte
recruitment and inflammation
Repertoiresynergism
Garlanda et al Nature 2002; Deban al Nature Immunol 2010; Lu et al Nature 2009; Bottazzi et al Annu Rev Immunol 2010;Doni et al J Exp Med 2015; Bottazzi et al PLOSOne 2015; Chorny…Cerutti JEM 2016; Garlanda et al Physiol Rev 2018
PTX3 as an extrinsic oncosuppressor in mouse and
human cancer: role of Complement
Bonavita et al Cell 2015; Rubino et al Oncoimmunology 2017;Reis et al Nature Rev Immunol 2018
Genetic or
Complement and PTX3 in 3-MCA carcinogenesis and selected human tumors (e.g. CRC; leiomyosarcoma..)
Bonavita et al, Cell, 2015; Rubino et al Oncoimmunol. 2018;Magrini et al unpublished; Reis et al, Nature Rev Immunol, 2018;Ruben Pio et al Frontiers Immunol in press
Complement
PTX3 (extrinsic oncosuppressor)
Recruitment-
M2-like
TAM
+
-
Tumor promotion
Inhibition of Immunotherapy
T
T
The macrophage balance in cancer
(Mantovani et al, Nature Rev. Clin. Oncol., 2017; Mantovani and Longo,New England J Med., 2018; Mantovani et al, Annu Rev Pathol, Under revision)
IL-1R8/TIR8/SIGIRRA member of the IL-1 receptor family, with regulatory function
IL-1 IL-33 IL-36 IL-18 IL-37 TLR ag
(for a review on IL-1/IL-1R family: Mantovani, Molgora, Dinarello and Garlanda, Immunity 2019;for IL-37R: Li et al PNAS; Nold-Petri et al Nature Immunol 2016)
IL-1R8/TIR8/SIGIRRA member of the IL-1 receptor family, with regulatory function
IL-1 IL-33 IL-36 IL-18 IL-37 TLR ag
(for a review on IL-1/IL-1R family: Mantovani, Molgora, Dinarello and Garlanda, Immunity 2019;for IL-37R: Li et al PNAS; Nold-Petri et al Nature Immunol 2016)
IL-1R8-deficient mice are protected against HCC development
Fig.6
0
1
2
3
4
5
6 10 12
Il1r8+/+
Il1r8 -/-
*
**
Liv
er M
acro
sco
pic
sco
re
Months after DEN
0
1
2
3
4
5
Liv
er
ma
cro
sco
pic
sco
re
isotype α-NK1.1
*****
Il1r8+/+
Il1r8 -/-
ns
ns
6
10
12
Il1r8+/+ Il1r8-/-
Il1r8+/+ Il1r8-/-
isoty
pe
α-N
K1.1
0
10
20
30
IFNγ
+ N
K c
ells (%
) *
0
10
20
30
ns
Il1r8+/+
Il1r8 -/-
Liver Spleen
0
5
10
15
NK
1.1
+ /
CD
45
+ c
ells (
%)
**
A
CB
D
NKp46
Il1r8 -/-
Il1r8 +/+
Model of DEN-induced hepatocellular carcinoma (HCC)
DEN-induced liver cancerogenesis NK cell infiltrate in the liver
6 Months 8-10 Months 12 Months
Il1r8+/+Il1r8+/+ Il1r8+/+Il1r8-/- Il1r8-/-
Il1r8-/-
(Molgora, Bonavita et al, Nature 2017)
NK cells express high levels of IL-1R8IL
1R A
cp
IL36
R
IL18
RIL
1RI
IL1R
IIST2
IL1R
80.000
0.002
0.004
0.006
0.05
0.10
0.15
0.20
mR
NA
re
lativ
e e
xpre
ssio
n
NK
mon
ocyt
es
mac
roph
ages
0.0000
0.0025
0.00500.025
0.050
IL1
R8
mR
NA
re
lativ
e e
xpre
ssio
n
CD56
br CD16
-/-
CD56
br CD16
+/-
CD56
dim CD16
+/+
CD56
dim CD16
-/-0.0
0.1
0.2
0.3
0.4
0.5
IL1
R8
mR
NA
re
lativ
e e
xpre
ssio
n
*
0
2
4
6
8
0
10
20
30
Bone Marrow Spleen Blood Liver
NK
ce
lls (
% o
n ly
mp
ho
cyte
s) *
*
DN
CD11
blo
wDP
CD27
low
0.0
0.2
0.4
0.6
0.8
1.0
Il1r8
mR
NA
re
lativ
e e
xpre
ssio
n
*
***
**
*
CD56
br CD16
-
CD56
br CD16
+/-
CD56
dim CD16
+/+
CD56
dim CD16
-/-
tota
l NK
0
20
40
60
80
IL-1
R8
re
lativ
e e
xpre
ssio
n (
MF
I)
**
0
20
40
60
NK
ce
ll su
bse
ts (%
on
tota
l NK
)
CD11blow DP CD27low
** **
0
20
40
60
80
100
NK
ce
ll su
bse
ts (%
on
tota
l NK
)
CD11blow DP CD27low
*** ***
***
0
20
40
60
80
100
NK
ce
ll su
bse
ts (%
on
tota
l NK
)
CD11blow DP CD27low
*** *
***
0
20
40
60
80
100
CD49b- CD49b+
NK
ce
ll su
bse
ts (
% o
n to
tal N
K)
Il1r8+/+
Il1r8 -/-
9.8
4.3
46.9
2.8
25.1
4.7
24.5
45.7
Fig.1
82.8
4.3
9.9
2.8
71.9
CD
56
CD16
gated on CD56 + CD3-CD56bri ghtCD16- CD56bri ghtCD16+/-
CD56dim CD16+/+ CD56dim CD16-/-
2.77
23.6
1.74
69.2
4.3
14.7
2.8
54.5
2.5
38.6
4.4
76.9
22.8
CD
11b
CD
11b
CD
11b
CD
49b
CD27 CD27 CD27 NK1.1
il1r8 +/+ il1r8 -/- il1r8 +/+ il1r8 -/- il1r8 +/+ il1r8 -/-
gated on CD56 + CD3-
isotype
IL-1R8
86.3
13.5
Bone Marrow Spleen Blood Liver
il1r8 +/+ il1r8 -/-
18.2
19.5
9
53.3
0
20
40
60
80
KL
RG
1+ N
K c
ells
(%
) ** *
SpleenBlood
**
Bone
Marrow
Il1r8 -/-Il1r8+/+
Spleen BloodBone
Marrow
KLRG1
isotype
IL-1R8
isotype
Il1r8+/+
Il1r8-/-
ISOTYPE aIL-1R8
Polentarutti N. et al, Eur. Cytokine Netw. (2003)
HUMAN protein expression
HUMANmRNA expression
MURINEmRNA expression
(Molgora, Bonavita et al Nature 2017)
See also Serhan … Miller, Cancer Immunol Res,
2018; Treg/IL-37 – IL-1R8/NK
Molgora, Bonavita et al, Nature, 2017;
Mantovani et al, Immunity, 2019, in press
Treg Treg
IL-1R8 AS A KEY REGULATOR (CHECKPOINT) OF NK
CELL DIFFERENTIATION AND FUNCTION
The Yin Yang of IL-1R8 in carcinogenesis and metastasis
Tumor promotingINFLAMMATION
IL-1R8 (TIR8/SIGIRR)
-ORGAN
IMMUNOLOGICAL CONTEXT
CHECKPOINT IN NK CELLS
UNLEASHED NK CELLS CAN MEDIATE RESISTANCE
AGAINST SOLID TUMORS AT NK RICH ANATOMICAL SITES
(Molgora, Bonavita et al Nature 2017;
Campesato et al Oncotarget 2018)( Riva et al Cancer Immunol. Res. 2019 in press)
Profiling human monocyte-to-macrophage differentiation and polarization
Mattiola, … Mantovani and Locati, Nature Immunol, in press
Mantovani, Locati, Cassatella, Immunity, 2009
Neutrophil alphabet
PTX3
Morgan AS and Yang DT, Blood 2013; 121:3546
NEVER UNDERESTIMATE THE POWER OF A NEUTROPHIL!
HIIS 2009-2014; Phii 2015-2020
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